The thermogenic effect of leptin is dependent on a distinct population of prolactin-releasing peptide (PrRP) neurons in the dorsomedial hypothalamus (#48)

The adipose-derived hormone, leptin,
is a critical regulator of metabolism, that acts through the long form of its
receptor, Lepr, within the brain to reduce energy intake, and to increase
energy expenditure by adaptive thermogenesis. The cellular pathways mediating
the anorectic actions of leptin have been identified, but those mediating the
thermogenic effects have proven difficult to decipher. Here we identify a specific
population of neuron in the dorsomedial hypothalamic nucleus (DMH), containing
the RFamide neuropeptide, PrRP, which is sensitive to leptin signalling. A
separate population of leptin-insensitive PrRP neurons in the brainstem is
required, instead, for the satiating actions of the gut-derived hormone,
cholecystokinin (CCK). Mice homozygous for a loxSTOPlox-PrRP allele are obese and do not respond
to leptin or to CCK. Cre recombinase-mediated reactivation of PrRP only in brainstem neurons rescues
the anorectic actions of CCK, but reactivation also in the hypothalamus is
required to re-establish the thermogenic effect of leptin. PrRP neurons in the
DMH respond to leptin injection, and knock out of Lepr selectively in these
cells blocks leptin’s ability to induce adaptive thermogenesis, reducing energy expenditure and resulting in
obesity. Thus, these data identify a distinct population of PrRP neuron in the
hypothalamus that is required for the thermogenic actions of leptin, separate
from the brainstem population mediating the satiating effects of CCK.